From Euphoria to Cardiac Stress: Role of Oxidative Stress on the Cardiotoxicity of Methylone and 3,4-DMMC

Synthetic cathinones (SCs), commonly referred to as "bath salts", are a class of novel psychoactive substances (NPSs) that elicit amphetamine-like effects and severe cardiovascular outcomes, including myocardial infarction and sudden cardiac death. Despite these risks, the mechanisms underlying SC-induced cardiotoxicity remain poorly studied. This study investigated the in vitro cardiotoxicity of two prevalent SCs-methylone and 3,4-dimethylmethcathinone (3,4-DMMC)-in H9c2 rat cardiomyoblasts, focusing on oxidative stress and the potential protective role of antioxidants. Cells were exposed to methylone (0.01-4.0 mM) or 3,4-DMMC (0.0005-0.8 mM) for 24 and 48 h, and cytotoxicity was assessed by an MTT assay. Intracellular reactive oxygen/nitrogen species (ROS/RNS) were quantified by fluorescence, and antioxidant effects were evaluated using ascorbic acid, N-acetylcysteine, and Trolox. Both SCs caused concentration-dependent cytotoxicity, with 3,4-DMMC showing higher potency than methylone (IC₅₀: 0.28 vs. 0.98 mM, <i>p</i> = 0.0013). ROS/RNS levels increased in a concentration- and time-dependent manner for both compounds, reflecting early and sustained redox imbalance. Of the antioxidants, only ascorbic acid significantly improved cell viability. Taken together, these findings demonstrate for the first time that methylone and 3,4-DMMC exert cardiotoxic effects in vitro, with oxidative stress as a key contributor. The protective effect of ascorbic acid highlights its potential as a therapeutic candidate against SC-induced cardiac injury.